ABSTRACT:
Objective. Prevalence studies indicate a 10-fold higher rate of
Tourette syndrome (TS) among children compared with adults. The purpose
of this investigation was to examine the course of tic severity during
the first 2 decades of life.

Method.
A birth-year cohort of 42 TS patients followed at the Yale Child Study
Center was recontacted an average of 7.3 years after their initial
clinical evaluation. Data concerning the onset and course of tic
severity until 18 years of age were available on 36 TS patients. A
variety of statistical techniques were used to model aspects of the
temporal patterning of tic severity.

Results.
Mean (SD) tic onset at 5.6 (2.3) years of age was followed by a
progressive pattern of tic worsening. On average, the most severe
period of tic severity occurred at 10.0 (2.4) years of age. In eight
cases (22%), the frequency and forcefulness of the tics reached a
severe level during the worst-ever period such that functioning in
school was impossible or in serious jeopardy. In almost every case this
period was followed by a steady decline in tic severity. By 18 years of
age nearly half of the cohort was virtually tic-free. The onset of
puberty was not associated with either the timing or severity of tics.

Conclusions.
A majority of TS patients displayed a consistent time course of tic
severity. This consistency can be accurately modeled mathematically and
may reflect normal neurobiological processes. Determination of the
model parameters that describe each patient's course of tic severity
may be of prognostic value and assist in the identification of factors
that differentially influence the course of tic severity.

Epidemiologic
studies have indicated a higher prevalence rate of Tourette syndrome
(TS) among children compared with adults. In children, prevalence rates
as high as 50 per 10 000 have been reported. [n1,n2] Studies of
adolescents and young adults have reported lower rates in the range 0.5
to 4.3 per 10 000. [n3-n5] In the one study that ascertained rates for
both children and adults, using identical methods, a 10-fold difference
was observed. [n4,n6] The reasons underlying this change in prevalence
are not well-understood but likely reflect age-related variations in
the natural history of the disorder that directly affect case
ascertainment. [n7,n8]

By
early adulthood, follow-up studies have consistently reported
improvement in tic severity for a majority of TS patients. [n9-n11]
Although a rough time course of tic severity has emerged, age-specific
estimates of tic severity have not been reported. Typically, natural
history studies of TS have included patients across a broad age range
with widely varying follow-up intervals. [n12] This cross-sectional,
observational approach combined with the failure of most studies to
identify key time points in the course of tic severity has made
cross-patient comparisons difficult.

Gender-
and stress-related hormonal factors have been implicated in the
pathogenesis of TS. [n13-n16] Although speculation has focused on the
role of gonadal androgens during the earliest stages of central nervous
system (CNS) development in utero, [n16,n17] anecdotal case reports and
evidence from clinical trials with antiandrogens support the view that
alterations in the hormonal milieu during adolescence and adulthood can
modulate tic severity. [n18-n20]

The
present study was undertaken to document the time course of tic
severity during the first 2 decades of life using data from a single
birth-year cohort of TS patients. A birth cohort was selected to
maximize our ability to make developmentally uniform cross-patient
comparisons. In our analytic approach, we used a variety of statistical
procedures to model these data to estimate the age of tic onset, the
age when the tics were at their worst, as well as other model
parameters. This model was then used to evaluate the a priori
hypothesis that pubertal onset is associated with either the timing or
degree of worstever tic severity.

METHOD

Subjects

Subjects
in this study consisted of 36 patients with TS who had been diagnosed
and evaluated at the Yale Child Study Center (YCSC) Tic Disorders
Clinic. Subjects were selected on the basis of their participation in a
case-control study of TS in which extensive data were collected
concerning the time course of tic severity. This study identified all
TS patients born in 1975 who had ever been evaluated at this YCSC
clinic. All patients were initially diagnosed with the Diagnostic and
Statistical Manual of Mental Disorders, 3rd ed (DSM-III) or 3rd ed,
revised criteria for TS using previously described methods. [n21] A
total of 42 TS cases were ascertained. Of this number, 36 cases (86%)
had sufficient information to be included in these analyses (32 males
and 4 females).

Procedures and Measures

Demographic
and clinical information was collected from four sources: the clinic
chart, a preliminary telephone interview with a parent, two in-person
interviews with a parent, and an in-person interview of the TS patient.

Chart Review

A
clinician with extensive experience with TS families (K.L.) abstracted
information from the clinical record using a precoded form. Data
recorded included demographic information; diagnostic status with
regard to TS, attention deficit-hyperactivity disorder (ADHD),
obsessive-compulsive disorder (OCD), and other comorbid conditions; and
age of onset and severity at presentation of TS, ADHD, and OCD.
Severity ratings were made using eight point ordinal Clinical Global
Impression (CGI) scales previously developed at the YCSC for each of
these disorders. [n21] Relevant points on the TS-CGI scale include:
mild severity, where the tic symptoms are judged not to interfere and
not to be noticeable to most people; moderate severity, where the tics
cause some problems in some areas of functioning (self-esteem, home
life, peers relations, and/or school performance) and are noticeable to
some people outside the family some of the time; marked severity, where
the tic symptoms cause clear problems in more than one area of
functioning and are frequent and quite noticeable in most situations
most of the time; and severe, where the tic symptoms because of their
frequency and forcefulness cause significant impairment in one or more
area, such that functioning in usual settings is impossible or in
serious jeopardy.

One
clinic chart could not be located, but the case was clearly identified
in the clinic roster permitting the case to be recontacted. In 10
randomly selected cases, another member of the research team (J.F.L.)
independently reviewed the same record. Comparisons of age at
evaluation, diagnostic status, age of onset, and scores on the
respective CGI scales revealed a high level of agreement (Pearson
correlations for age of tic onset and age at evaluation were r = 0.98
and r = 0.83, respectively). The interrater agreement for a diagnosis
of TS was perfect, and the k statistic values for the Diagnostic and
Statistical Manual of Mental Disorders, 4th ed (DSM-IV) diagnoses of
OCD and ADHD were excellent (0.83 and 0.77, respectively). The Spearman
rank order correlations for the CGI scores were also excellent (ranging
from p = 0.79 to p = 1.00). A comparison of data abstracted from the
initial clinic evaluations of the 36 cases included in this analysis
and the 6 remaining cases revealed no statistically significant
differences with regard to age at evaluation, sex, socioeconomic status
(SES), age of tic onset, or tic severity at initial evaluation.

Initial Follow-up Interview

After
an initial letter describing the study and requesting consent, parents
were contacted by telephone and inquiries were made concerning current
demographic information; the history of the family's contact with the
YCSC Tic Disorders Clinic; data concerning their child's tic disorder
(age of onset, age when tics were at their most severe, medication
history, and a rating of current tic severity using the Yale Global Tic
Severity Scale [YGTSS] [n22]; comparable data concerning ADHD and OCD;
and data concerning the onset and duration of puberty). The YGTSS is a
standard clinical rating instrument for TS with excellent interrater
agreement and other favorable psychometric properties including a high
correlation with the TS-CGI scale. [n22] A slightly modified and
expanded form of the YGTSS was used in the telephone interview portion
of the study. [n23] This version has previously been shown to have a
high level of agreement with YGTSS ratings independently made by
experienced clinicians. [n23], At the conclusion of the interview,
families were invited to participate in a more in-depth in-person
interview to take place in the family's home. Interviewers were blinded
to the information abstracted from the chart record.

Parent Interviews

After
signed informed consent, parents participated in four semistructured
in-person interviews. In the first interview, parents again reported on
the course of their child's tic disorder (ratings of current and
worst-ever tic severity using the YGTSS, annual rating of relative tic
severity (ARRTS) using a 6-point ordinal scale (absent, least severe,
mild, moderate, severe, and most severe) from which age of tic onset,
and age of most severe tic symptoms were transcribed, and a current
medication history). During the second interview, parents reported on
comorbid conditions using a semistructured interview, the Schedule for
Tourette and Other Behavioral Syndromes, Adult-on-Child Version,
Revised (STOBS-R) that has been extensively used in family-genetic
studies. [n24,n25] The STOBS-R also contains information concerning the
onset of puberty. The third interview focused on putative risk factors,
a main focus of the formal case control study, and used the Modified
Schedule for Risk and Protective Factors (MSRPF) developed by John T.
Walkup, J.F.L., and B.S.P. [n26] In the final interview, parents were
asked about their own tic histories as well as other psychopathology
using the STOBS-R, child version. Because of the requirements of the
case control study, different interviewers conducted the MSRPF and
remained blinded to the information concerning tic severity. The
results of the case-control aspects of this study will be reported
elsewhere.

Patient Interview

The
TS patient was interviewed in-person using the STOBS-R. This
information was supplemented by current and worst-ever ratings of tic
severity based on the YGTSS.

Best Estimate Diagnoses

All
available diagnostic information on TS patients and their parents were
blindly and independently evaluated by two investigators (J.F.L. and
B.S.P.). The resulting DSM-IV diagnostic ratings were compared and
discrepancies were resolved using a previously described consensus
procedure. [n27]

Data Analysis

Data
analysis was conducted in several stages. An initial aim was to
describe the sample and compare ratings across the three time points
(clinical evaluation, initial follow-up interview, and in-person
interviews with parents and patients). The test-retest reliability of
key ratings of tic onset, timing of worst-ever tic severity, current
and worst-ever tic severity (using the YGTSS) were then evaluated in an
effort to validate the ARRTS.

Examination
of the time course of the tic severity curves derived from the ARRTS
ratings for individual TS patients led to the development of a
mathematical model of tic severity characterized by the identification
of an initial point of tic onset, followed by a period of increasing
tic severity, followed by an inflection point (corresponding to the
period of worst-ever tic severity), after which the tic severity
steadily declined. A statistical bootstrapping technique was then used
to assess the variability of the estimates for each model parameter.
[n28]

Once this
model was established, the hypothesis that the course of tic severity
is related to the timing of puberty onset was evaluated by including
the main effect of the age of puberty onset and its interaction terms
in the model. This computation was carried out in SAS using PROC MIXED
(SAS, Cary, NC).

RESULTS

On
average, the 36 members of the YCSC 1975 birth cohort were evaluated at
age 11.0 years (range: 5.9-16.9; SD: 2.9). The initial telephone
follow-up interview occurred when the TS patients were, on average,
17.7 years of age (range: 17-20; SD: 0.7); and the in-person interviews
with the parents and the TS patients took place when the patients were,
on average, 18.4 years of age (range: 17-20; SD: 1.0). The average
interval between the initial YCSC evaluation and the in-person
interviews was 7.5 years (range: 1.2-12.1; SD: 2.7). All 36 patients
met DSM-IV criteria for Tourette disorder. Of this number, 25 (69%) met
lifetime DSM-IV criteria for ADHD (combined type-16 (44%), inattentive
type-8 (22%), and hyperactive/impulsive type - 1 (3%)). Another 13
(36%) cases met lifetime DSM-IV criteria for OCD. Most the families
were middle-class. The mean SES status of the families was 47.9 (range:
27-64; SD: 10.6).

Current Tic Status

At
the time of the in-person interviews, when the TS patients were 18
years of age, tic symptoms for a majority of the 36 cases were minimal
or absent. On average, the total tic score of the YGTSS assessed at the
time of the in-person interviews with the parents and patients was 7.92
(actual range: 0-30 [possible range: 0-50]; SD: 9.53). Seventeen
patients (47.2%) were entirely tic-free during the week before the
in-person interviews. Another 4 patients (11.1%) had minimal tic
symptoms (YGTSS total tic score of <10). Ten patients (27.7%) had
mild symptoms (YGTSS total tic score of >/= 10 but <20), and only
4 patients (11.1%) were judged to have a moderate or marked level of
tic severity (YGTSS total tic score of >/=20 but <40).

Severity and Timing of Tics During the Worst Period

On
average, the worst-ever total tic score on the YGTSS estimated at the
time of the in-person interview was 29.8 (range: 4-49; SD: 10.9). Based
on the frequency and forcefulness of their tics, 8 patients (22.2%)
were judged during their worst period to have severe tics (YGTSS total
tic scores >/=40 but <50) that were associated with a significant
impairment in their primary social role such that functioning in usual
settings was impossible or placed in serious jeopardy. Ten patients
(27.8%) were judged during their worst period to have marked tic
severity (tics frequent and quite noticeable in most situations most of
the time; YGTSS total tic scores >/=30 but <40). Fourteen
patients (38.9%) were judged during their worst period to have moderate
tic severity (tics cause some problems and are noticeable to some
people some of the time; YGTSS total tic scores >/=20 but <30).
Only 4 patients (4.0%) were judged to have a mild level of tic severity
during their worst period (YGTSS total tic score of <20).

Based
on data collected during the initial telephone follow-up and the
in-person interviews, the worst tics occurred between the ages of 6 and
15 years (mean: 10.0; SD: 2.4). Figure 1 presents a histogram of these
data by year. The level of tic severity during the worst period was
positively associated with the patient's age during the worst-ever
period (Fig 2; Pearson r = 0.58, N = 34, P < .0001).

Predictive Value of Earlier Estimates of Tic Severity

Nine
cases were judged to have mild tics during their initial clinic
evaluation. Among this group, 3 cases continued to have only mild
symptoms during their worst period. In each of these cases, no tics
were evident at the time in-person interviews. In another 4 of the
initially mild cases, their worst-ever tic severity was rated as
moderate, and at the time of the in-person interviews tics were either
absent (N = 2), minimal (N = 1), or mild (N = 1). Surprisingly, 2 cases
judged to have mild tic severity at their YCSC evaluation were judged
to have severe tic severity during their worst period, but fortunately
in both cases at the time of the in-person interviews, their tic
symptoms were either mild (N = 1) or moderate (N = 1) in severity.

Sixteen
cases were judged to have moderate tic severity at the time of their
initial YCSC evaluation. Among this group, 7 cases were judged to have
either moderate (N = 6) or mild (N = 1) tic severity at the time of
their worst symptoms. At the time of the in-person interviews, 5 of
these cases were tic-free, 1 case had mild symptoms, and only 1 case
continued with a moderate level of tic severity.

Of
the 9 initially moderate cases remaining, 6 were judged to have marked
tic severity during their worst period and 3 were judged to have severe
tics. In this subgroup at the time of the in-person interviews, 1 case
showed no tic symptoms, 3 had minimal symptoms, 4 had mild, and only 1
case continued with a moderate level of tic severity.

Ten
cases presented at the time of their initial YCSC evaluation with a
marked level of tics. Seven of these cases were judged to have either
moderate (N = 3) or marked (N = 4) tic severity at the time of their
worst symptoms. In this subgroup, 3 cases were tic-free at the time of
the in-person interviews, three cases were rated has having mild tic
severity, and in only 1 case did the tic severity remain at a marked
level. The 3 remaining cases with marked severity at the time of their
initial evaluation all had severe tic symptoms during their worst
period. Remarkably, 2 of these cases showed no tic symptoms during
their in-person interviews, and the remaining case had a mild level of
tic severity at follow-up.

A
majority of TS patients displayed a consistent time course of tic
severity. This consistency can be accurately modeled mathematically and
may reflect normal biological processes that occur during the course of
brain development. Using the ARRTS data collected at the time of the
in-person interviews, individual growth curves of tic severity were
generated. Figure 3 presents the mean and SDs of these curves.

In
an effort to validate key points along this composite curve,
test-retest comparisons were made between the age of onset estimates
made at the time of the initial YCSC evaluation, at the initial
telephone follow-up interview, and the onset point derived from the
ARRTS curves. The mean values for each of these estimates showed a high
level of agreement (mean [SD] age of tic onset: estimated from the
chart review: 5.8 years (1.7); from the initial telephone follow-up
interview: 5.8 years (2.8); and from the ARRTS curves: 6.0 (2.7)). The
test-retest reliability of these estimates was reasonably good (ARRTS
estimate vs initial telephone follow-up: Pearson r = 0.67, N = 31, P
< .0001; and ARRTS estimate vs chart review data: Pearson r = 0.58,
N = 32, P < .0001). Fewer estimates were available to judge the
testretest reliability of the age of worst tic symptoms. The mean
values for each of these estimates showed a good level of agreement
(mean [SD] age of worst tic severity estimated from the initial
telephone follow-up interview: 10.0 years (2.4); and from the ARRTS
curves: 10.8 (3.1)). However, the test-retest reliability of these
estimates, was only fair (ARRTS estimate vs initial telephone
follow-up: Pearson r = 0.48, N = 31, P < .007).

Descriptively
in 2 of the TS cases, the ARRTS curves had 2 points of maximal severity
(relative tic severity = 5) separated by a period of 1 year or longer
when the symptoms were not as severe. In both cases, rather than taking
a mean value of these 2 points (and by doing so identifying a point in
time when their tics were not as bad as either of the worst-ever
points) a convention was established so that a worst-ever time point
was selected on the basis of which period was of the longer duration.
In another 5 cases, parents identified relative maximums in tic
severity (relative tic severity <5) indicating a fluctuating course.

Mathematical Model of the Time Course of Tic Severity

Given
the consistent time course of tic severity across patients, we
formulated a mathematical model to describe precisely this pattern.
This process is akin to comparing a patient's growth curve for height
or weight to a composite curve for a larger number of patients. Based
on an examination of the individual and composite ARRTS plots, the
ARRTS data were partitioned into three segments. Let t denote age in
years. The tic time course, f(t) is characterized by: [[alpha]t if t </= [tau][1] f(t) = [[beta][0] + [beta][1]t + if [tau][1] < t </= [tau][2] (1) [beta][2]t<2> [[gamma][0] + [gamma][1]t if t > [tau][2]

where
[tau][1] refers to the age-at-onset and [tau][2] is closely related,
but not necessarily equal, to the age at which their tics were at their
worst. Table 1 displays the parameter distributions of the tic time
course function obtained from the bootstrap procedure. [n28] A plot of
this function is included in Fig 3. Individual growth curves were also
generated. Mean values for each of the parameters obtained from
individual curves were in close agreement with estimates obtained by
bootstrap methods.

TABLE 1. Parameters for the Time Course of Tic Severity FunctionParameters Mean (SD)

The
present study was undertaken, in part, to evaluate the a priori
hypothesis that pubertal onset is associated with the period of
worst-ever tic severity. This hypothesis was not supported in this
group of patients. Age at pubertal onset was not associated with the
age when the tics were at their worst (r = 0.02, NS) or degree of
worst-ever tic severity (r = 0.08, NS). Similarly, when the timing of
puberty onset was included in the time course model (Fig. 3), neither
its main effect nor its interactions with any of the other parameters
were significant.

In
an effort to validate the age of pubertal onset, test-retest
comparisons were made between the age of pubertal onset estimates made
at the time of the initial telephone follow-up interview and during the
in-person parental interview. The mean values for each of these
estimates showed a high level of agreement (mean [SD] age of puberty
onset: estimated from the initial telephone follow-up interview: 13.0
years (1.3); and the direct parental interview: 13.7 (1.7)). The
test-retest reliability of these estimates was also reasonably good
(direct parental interview estimate vs initial telephone follow-up:
Pearson r = 0.67, N = 31, P < .0001).

DISCUSSION

The
natural history of TS and other chronic tic disorders is not
well-understood. In this report we present an explicit model of the
time course of tic severity over the first 2 decades of life. This
model extends the findings of previous follow-up studies by offering
agespecific tic severity estimates and by defining a period of maximal
tic severity that usually occurs between the ages of 8 and 12. [n7-n11]
If confirmed, this pattern of ascending severity followed by a near
linear decline may also clarify the differences in TS prevalence that
are found when adult versus child populations are studied using similar
methods. [n4,n6] By early adulthood, tic severity may have declined
sufficiently that a TS diagnosis may no longer be warranted.

Before
discussing the clinical implications of this study and its potential
value, we should take note of its limitations. Recall bias may have
influenced the parents' and the patients' reporting. Our use of
testretest procedures to determine the reliability of key informants
and the use of blinded interviews of multiple informants (parents vs
patients) support the accuracy of our findings. The documented decline
in the YGTSS ratings from the initial telephone follow-up to the time
of the in-person interviews directly supports the validity of the ARRTS
ratings. Likewise, the consistency of the parental reports (in only 3
cases was there an inconsistency between the level of tic severity
observed at evaluation and the family's estimate of tic severity during
the worst period) lends support to validity of the time course of tic
severity that emerges from this report.

A
limitation concerning the mathematical modeling approach is that in a
small number of cases (N = 2) more than one worst-ever time point was
reported. In 5 other cases, relative maximums in tic severity were
reported. Rather than seeing these as exceptional cases, it is probably
better to consider the unimodal distributions of relative tic severity
(seen in all the remaining cases) as being composed of multiple
relative maximums in tic severity that are undetectable at this level
of temporal scaling. This view is supported by the well-known waxing
and waning pattern of tics that occur over weeks to months. This
discussion raises the potentially important point that the temporal
occurrence of tics may be determined by nonlinear dynamical processes.
[n29] One of the characteristic features of these nonlinear, chaotic,
systems is that they are fractal in nature -- that regardless of the
temporal scaling (seconds, hours, weeks, months, years) a similar
bursting intermittency is evident. [n30] The tics occur in bouts, the
bouts of tics occur in larger superbouts, and so forth. Viewed from
this perspective, the unimodal tic severity curves seen in this study
may be a reflection of the same processes that underlie both the
occurrence of tics in bouts (temporal scaling at the level of seconds
and milliseconds) and their waxing and waning pattern (temporal scaling
at the level of weeks to months).

The
processes that underlie tic onset and the usual time course of tic
severity are largely unknown. Hormonal and neurochemical factors active
early in CNS development have been the subject of speculation.
[n16,n17,n31] For example, exposure of the developing CNS to gonadal
steroids has been implicated. [n17-n19] Although indirect evidence from
this study may argue against increasing levels of gonadal androgens
during male pubescence as a major risk factor for tic exacerbation, the
complexity of hormonally mediated events in the brain surrounding
adrenarche and puberty urge caution. [n32] The consistency of the
pattern observed across patients strongly suggests the presence of an
underlying process. It is intriguing to speculate that this time course
may reflect neurobiological events that normally occur during the
course of brain development and that are overtly expressed only because
of the patient's TS vulnerability.

Caution
is warranted in the interpretation of the data concerning puberty onset
because these data were not ascertained directly by physical
examination or Tanner staging. If confirmed in subsequent studies, the
data presented in this report may influence clinical practice. In our
experience, families find comfort in the realization that tic severity
will likely decline through adolescence. Such knowledge is likely to
help families and pediatricians live with the tics and to delay the
decision to begin psychotropic medications. Ages 8 through 12 are
likely to be critical. If medications can be avoided through this
period, the patient may have a good chance of never needing them.
Although anti-tic medications are available, none are ideal. Over the
longer term, starting medications may do more harm than good, given
their potential adverse effects and the difficulties associated with
medication withdrawal. This is particularly true of the standard
neuroleptic agents such as haloperidol and pimozide. [n33]

As
discussed by Goetz and co-workers, [n8] it is important to be mindful
that tic severity early on is not necessarily a good predictor of later
tic severity. For example, 20% of the mild cases at clinic evaluation,
went on to have severe tics. More importantly, 90% of the patients with
marked tic severity at evaluation had mild or no tics by 18 years of
age. The finding of an association between age of the patient when
their tics were at their worst and the level of tic severity during
that same period may have limited predictive value except when older
adolescents present with severe tic symptoms -- heralding a relatively
poor prognosis.

The
results of this study only extend to the end of the second decade. A
minority of TS patients go on to have catastrophic outcomes in
adulthood. Whether any of the parameters examined in this study have
predictive value for the early identification of these individuals
awaits further investigation.

ACKNOWLEDGMENTS

This
research was supported by a grant from the March of Dimes (to B.S.P)
and National Institutes of Health Grants MH-01232, MH-49351, MH-44843,
MH-30929, HD-03008, HD-30712, and RR-06022.

We
thank Drs Christopher R. Canny, Priscilla F. Canny, Donald J. Cohen,
Diane Findley, Robert A. King, Robert A. Makuch, David L. Pauls, and
Lawrence Scahill, and Sharon Ort for their assistance and comments on
an earlier draft of this report.

SUPPLEMENTARY
INFORMATION: From the <1> Child Study Center, the Children's
Clinical Research Center, and the Departments of Pediatrics and
Psychiatry; and the <2> Division of Biostatistics, the Department
of Epidemiology and Public Health, Yale University School of Medicine,
New Haven, Connecticut.

GRAPHIC:
Figure 1, Age distribution of when tic symptoms were at their worst.
This histogram presents the age at worst-ever tics as reported by
parents during in-person interview; Figure 2, Association of age and
level of worst-ever tic severity. This scattergram plots worst-ever tic
severity versus age at worst-ever tic severity and suggests a positive
association between these variables (Pearson r: 0.58, N = 34, P <
.0001); Figure 3, Plot of mean tic severity, ages 2 to 18 years. The
solid line connecting the small circles plots the means of the annual
rating of relative tic severity scores (ARRTS) recorded by the parents.
The dashed line was generated using the modeling equations (Table 1)
and the mean values for each of the coefficients and intercepts as
determined by a statistical bootstrapping technique. Two inflection
points are evident that correspond to the age of tic onset and the age
at worst-ever tic severity, respectively.